Survival Outcomes Among Patients With Gastric Adenocarcinoma Who Received Hyperthermic Intraperitoneal Chemotherapy With Cytoreductive Surgery

Gastric cancer (GC) with peritoneal metastases is associated with a poor prognosis. Median overall survival (OS) is less than 1 year with systemic chemotherapy alone.¹ Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) has been used for various peritoneal surface malignant tumors, and there has been marked interest in its application to GC because a small randomized clinical trial demonstrated improved OS among patients who underwent CRS-HIPEC compared with CRS alone.² Although widespread adoption of HIPEC for GC has been limited because of poor oncologic outcomes and high perioperative morbidity,³ interest in the use of intraperitoneal chemotherapy for patients with advanced GC persists.¹ We assessed survial outcomes among patients with gastric adenocarcinoma who received CRS-HIPEC at academic centers across the United States.

Patients with gastric adenocarcinoma identified on final pathology reports were identified from the US HIPEC Collaborative, a multi-institutional data set composed of more than 2300 patients from 12 academic medical centers. Institutional review board approval was obtained at each participating institution. A retrospective analysis of baseline demographic, clinicopathologic, operative, and postoperative factors was performed using descriptive statistics. Both OS and recurrence-free survival were analyzed using the Kaplan-Meier method. No informed consent was required because a waiver of informed consent was requested for this study given that it was a retrospective medical record review of data with no direct patient contact. Deidentified data were used for all distribution and analysis.

Overall, 28 patients (17 [61%] female; mean [SD] age, 48.5 [14.2] years) with GC underwent HIPEC at 7 institutions between January 1, 2010, and December 31, 2017. Baseline demographic and clinicopathologic factors are given in the Table. Twenty-five patients (89%) had overt peritoneal dissemination, whereas 3 (11%) had positive cytologic findings on peritoneal washings. The median peritoneal carcinomatosis index (PCI) of those with peritoneal disease was 12 (interquartile range, 4-17). Curative-intent resection was performed in 23 patients; 5 patients underwent palliative HIPEC. In the curative-intent population, complete cytoreduction was achieved in 16 (70%) of 23 patients. Twenty-seven patients (96%) received neoadjuvant or adjuvant chemotherapy. Although 17 chemotherapy regimens (63%) were fluorouracil based, 15 distinct regimens were observed. In the curative-intent population, median recurrence-free survival was 7 months (95% CI, 4.9-9.1 months) and OS was 10 months (95% CI, 6.5-13.5 months) (Figure, A and B). Improved median OS was observed among the 11 curative-intent patients with a PCI of 9 or less compared with the 12 patients with PCI scores greater than 9 (26 vs 8 months; P = .01). After palliative HIPEC, the median OS was only 2 months (range, 2-13 months).

Perioperative morbidity among all patients was high: 21 (75%) experienced at least 1 complication, 5 (18%) of which were Clavien-Dindo grade 3 or higher. Five patients required a subsequent operation for indications, including anastomotic leak, intra-abdominal infection, or obstruction. The need for nutritional support was common; total parenteral nutrition was required for 13 patients (46%), whereas 9 (32%) of 28 needed supplemental tube feeds. The median length of stay was 11 days (interquartile range, 8-15 days), and 7 patients (25%) required readmission. Two patients (7%) died within 90 days of surgery.

The optimal role for HIPEC in the treatment of advanced GC remains poorly defined.¹ Because of the lack of high-quality evidence, unclear criteria for patient selection, and biological differences among patients, no standardized approach has emerged. In addition, no clear survival advantage exists compared with results reported with standard chemotherapy alone, and little progress has been made in patient outcomes. More than a decade ago, published reviews^3,4 of European and US patients undergoing CRS-HIPEC for GC reported a median OS of 8.0 to 9.2 months, with a perioperative morbidity ranging from 27.8% to 35.0%. Comparable mortality and morbidity rates from our current series suggest that outcomes remain poor, even among experienced centers. Although multiple studies indicate there may be a survival benefit among patients with lower PCI scores, a consensus cutoff has not been determined.¹ Clear criteria to aid in patient selection remain elusive given the lack of high-quality evidence. Our study is limited by the overall low number of patients, selection bias arising from the retrospective design, and the lack of standardized treatment protocols across participating centers. Innovative approaches to this population, such as neoadjuvant laparoscopic HIPEC or combination intraperitoneal and intravenous chemotherapy, should be evaluated prospectively.^5,6 In the meantime, our findings suggest that HIPEC for GC should be limited to clinical trials and preferably restricted to patients with low PCI scores (scores ≤9).

Accepted for Publication: March 16, 2019.

Corresponding Author: Jordan M. Cloyd, MD, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 410 W 10th Ave, N-907 Doan Hall, Columbus, OH 43210 (jordan.cloyd@osumc.edu).

Published Online: June 12, 2019. doi:10.1001/jamasurg.2019.1698

Author Contributions: Dr Cloyd had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kimbrough, Pawlik, Cloyd.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kimbrough.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kimbrough.

Administrative, technical, or material support: Beal, Cloyd.

Supervision: Pawlik, Cloyd.

Conflict of Interest Disclosures: None reported.

Additional Information: US HIPEC Collaborative included the following individuals: Jennifer Leiting, MD, and Travis Grotz, MD (Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, Minnesota); Keith Fournier, MD, and Andrew Lee, MD (Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston); Sean Dineen, MD, and Jose Pimiento, MD (Department of Gastrointestinal Oncology, Moffitt Cancer Center, Department of Oncologic Sciences, Morsani College of Medicine, Tampa, Florida); Jula Veerapong, MD, and Joel M. Baumgartner, MD, MAS (Division of Surgical Oncology, Department of Surgery, University of California, San Diego); Callisia Clarke, MD, and Erin Strong, MD (Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee); Charles A. Staley, MD, and Mohammad Y. Zaidi, MD (Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia); Sameer H. Patel, MD, and Jeffrey Sussman, MD (Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio); Laura Lambert, MD, and Ryan J. Hendrix, MD (Division of Surgical Oncology, Department of Surgery, University of Massachusetts Medical School, Worcester); Daniel E. Abbott, MD, and Kara A. Vande Walle, MD (Division of Surgical Oncology, Department of Surgery, University of Wisconsin, Madison); Mustafa Raoof, MD, and Byrne Lee, MD (Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, California); and Fabian M. Johnston, MD, MHS, and Nadege Fackche, MD (Department of Surgery, Johns Hopkins University, Baltimore, Maryland).